The atherosclerosis is a process of degeneration of the arterial wall and represents the main cause of many vascular pathologies like ischaemic cardiopathies (angina pectoris and myocardial infarction) and cerebral thrombosis, main causes of death in the industrial countries.
Many efforts have been carried out to understand the aetiology of this pathology of wide diffusion and importance and to find out the possible therapeutical treatments.
The atherosclerosis is a process with composite aetiology that involves in varied measure different factors and cell types. Ross R. in New Engl. J. Med., 314, 488-495, (1986) assumes that the endothelial damages, caused by exposure to many risk factors, represent the main event in the genesis of the atheroma and in Amer. J. Pathol., 143, 987-1001, (1993) finds out an important cause of the induction of such endothelial damage and of the progress and complication of the atheromatous plaque in the high serum rates of lipids and cholesterol that characterize the hyperlipidaemias and that often aggravate the diabetic pathologies. The pharmacological interventions aimed at lowering the plasma levels of cholesterol and low density lipoproteins (LDL) have proved to be effective in the prevention of the vascular coronary pathologies and in the treatment of atheromatous plaques, as reported by Steinberg D. in J.A.M.A., 253, 2080-2086, (1985) and in Atherosclerosis, 3, 283-301, (1983). The atherogenic risk joined to the LDL appears bound together with not only their plasma concentration but also their qualitative characteristics; the possible modifications of the structure and composition of the LDL in the plasma or in the arterial wall can in fact make these macromolecules more atherogenic, namely more apt to trigger off and to stimulate the formation of the atheromatous plaque, as reported by Steinberg D. in New Engl. J. Med., 320, 915-924, (1989). The oxidative processes that occur by action of oxidizing agents present in the plasma or in the endothelial cells of the arterial wall are of main importance among the modifications that the LDL can undergo in vivo. Many in vitro and in vivo experiments, together with the results of epidemiological investigations, support the hypothesis that this mechanism represent a key event in the development of the atherosclerosis, as reported by Esterbauer H. et al. in Brit. Med. Bull., 49, 566-576, (1993).
In fact Steinberg D. in New Engl. J. Med., 320, 915-924, (1989) shows the presence of antibodies anti-OX-LDL and of OX-LDL, oxidized low density lipoproteins, in the atheromatous lesions of patients suffering from advanced atherosclerosis. Moreover Witzum J. L. and Steinberg D. in J. Clin. Invest., 88, 1785-1792, (1991) report that the OX-LDL are toxic towards the endothelial cells and show a pro-inflammatory activity towards monocytes and lymphocytes and an increased susceptibility to the taking from the macrophages and the smooth muscle cells with formation of foam cells. Such properties can have an important part in the processes of formation and progression of the atheromatous lesion, as reported by Ross R. in Nature, 362, 801-809, (1993).
The LDL are particles not only rich of cholesterol but also of fatty polyunsaturated acids, abbreviation PUFA, highly susceptible to the peroxidation from which they are protected by the presence of many endogenous antioxidizers like tocopherols, carotenes, lycopene and ubiquinol-10.
The oxidation of the LDL is a chain reaction of lipidic peroxidation led by free radicals able to quickly transform the PUFA into lipidic hydroperoxides (propagation period).
The endogenous antioxidizers challenge the chain of propagation by means of an effective scavenging of the peroxylic radicals and the concentration of hydroperoxides increases only when the endogenous antioxidizers are depleted (latency period).
The reactive species of oxygen that form during the process of oxidation together with monounsaturated aldehydes that stem from the decomposition of the hydroperoxides, mainly malondialdehyde (MDA) and 4-hydroxynonenal, cause important changes in the primary structure of the main LDL apoprotein, the B-100 apolipoprotein (apo B-100). Such modification, by helping the LDL absorption by the macrophages, causes the intracellular accumulation of esters of the cholesterol and the formation of foam cells with subsequent development of the atherosclerotic plaque, as reported by Vanderyse L., et al. in Atherosclerosis, 97, 187-199, (1992).
Steinberg D. et al. in Proc. Nat. Acad. Sci. USA, 84, 7725-7729, (1987) show how compounds with antioxidizing action towards the LDL can have a part as anti-atherosclerotic drugs. The effectiveness of a treatment by means of substances having antioxidizing action is based on observations limited to in vitro and animal models and on the in vivo use of the Vitamin E. In fact the atherogenic potentialities of the LDL are remarkably lowered in vitro when the LDL are incubated in presence of antioxidizers, like for instance probucol or Vitamin E, as reported by Esterbaur H. et al. in Amer. J. Clin. Nutr., 53, 314S-321S, (1991).
Studies carried out on Watanabe rabbits, suffering from familial hypercholesterolaemia and with high levels of LDL, showed that the treatment with probucol lowers the atheromatous lesions even if it does not substantially modify the LDL plasma levels, as reported by Kita T. et al. in Proc. Nat. Acad. Sci. USA, 84, 5928-5931, (1987).
Prospective studies on a large scale show a relation between the taking of considerable amounts of Vitamin E and the lowering of the risk of vascular pathologies, both in men and in women, as reported by Rimm E. B. et al. in New Engl. J. Med., 328, 1450-1456, (1993) and by Stampfer M. J. et al. in New Engl. J. Med., 328, 1444-1449, (1993). At present the therapy of the disorders of the lipidic metabolism, like the familiar heterozygotic hypercholesterolaemia, the combined familiar hyperlipidaemia, the dis-.beta.-lipoproteinaemia, the familiar hypertriglyceridaemia and the polygenic hypercholesterolaemia, that are important causes of the atherosclerosis, is based on the use of drugs having hypolipidaemic activity like the fibrates (for instance Gemfibrozil), the the acid, the resins sequestering the bile acids and the inhibitors of the enzyme HMGCoA reductase. The metabolic effect of these drugs is that of lowering the plasma concentration of cholesterol (LDL) and partly of the triglycerides (VLDL-LDL) through two mechanisms: an increase of the mediated receptor-removal of the LDL, or a lowering of the synthesis of the VLDL-LDL. Generally the best reductions of the plasma LDL have been obtained by means of the resins sequestering the bile acids and with the statins, inhibitors of the HMGCoA reductase, while the plasma levels of the triglycerides are mostly affected by the treatment with nicotinic acid and fibrates, as reported by Betteridge D. J. in Current Opinion in Lipidology, 4, 49-55, (1993). Therefore, on the basis of the above mentioned considerations, it is reasonable to suppose that molecules having both hypolipidemic and antioxidant activity represent a therapeutic development important in the treatment of the disorders of the lipoproteic metabolism and in the prevention of the atherosclerosis.
The compounds object of the present invention are endowed with antioxidant and hypolipidaemic properties, in particular they show the capability to prevent and/or to delay the oxidative modification of the LDL, i.e. they compete with the chain of propagation of the lipidic peroxidation through an effective scavenging of the peroxylic radicals.
The oxidative modifications of the low density lipoproteins (LDL) represent, as it has already been seen, a key event in the pathogenesis of the atherosclerosis and therefore the compounds object of the present invention can find useful therapeutical application in the treatment of the atherosclerosis and in the prevention of many vascular pathologies like ischaemic cardiopathies (angina pectoris and myocardial infarction), cerebral thrombosis and peripheral arteriopathies.